title: Melphalan as a treatment for BRCA-related ovarian carcinoma: can you teach an old drug new tricks?
abstract: Late-stage ovarian carcinoma is almost universally fatal. BRCA mutations are associated with an improved outcome and enhanced sensitivity to platinum chemotherapy, yet recurrence and platinum resistance remain a major problem and highly effective regimens following platinum failure do not yet exist. Here we report a remarkable case of cure following platinum-resistant stage III ovarian carcinoma in a woman with a BRCA2 mutation. The patient was subsequently treated with oral melphalan therapy and has not recurred in over 25 years. Melphalan is a bifunctional alkylator that creates inter- and intra-strand DNA cross-links. In a pharmaceutical screen, melphalan was shown to be selectively toxic to BRCA2-deficient breast cancer cell lines and produced a longer relapse-free survival in mice than did cisplatin or olaparib. There is increasing evidence to consider BRCA mutation status when selecting chemotherapy regimens, and melphalan treatment for BRCA-related ovarian cancer merits further investigation. Focusing attention on long-term survivors may provide new mechanistic insights into the biology of chemo-responsiveness.
authors.affiliation: Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Deidra J
authors.initials: DJ
authors.lastname: Osher
authors.forename: Yaël B
authors.initials: YB
authors.lastname: Kushner
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Arseneau
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D024682:BRCA2 Protein / Q000235:genetics*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008558:Melphalan / Q000627:therapeutic use*; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D008558:Melphalan